Fibrinogen (FBG) assembles into matrix fibrils of fibroblasts, lung and mammary epithelial cells, but not endothelial cells. Furthermore, cryptic ␤ 15-21 residues are exposed in FBG fibrils with no evidence of thrombin or plasmin proteolysis. Herein, the effects of FBG on migration and proliferation of wounded dermal fibroblasts were investigated. FBG preassembled into matrix prior to scrape-wounding induced 3 Hthymidine incorporation 8-fold and shortened the time to wound closure 1.6-fold ؎ 0.1-fold. FBG added immediately after wounding did not enhance either response. Fibroblast growth factor-2/ platelet-derived growth factor (FGF-2/ PDGF) stimulated cell proliferation 2.2-fold for FGF-2 and 3.2-fold for PDGF and wound closure 1.5-fold ؎ 0.1-fold in the absence of matrix-FBG. Surprisingly, exogenous growth factors had negligible effect on wound closure and cell proliferation already enhanced by matrix-FBG. Matrix-FBG-enhanced wound closure required active assembly of an FBGfibronectin matrix, engagement of ␣v␤3, and FBG A␣-RGDS 572-575 integrin recognition sites; A␣-RGDF 95-98 sites were not sufficient for matrix-FBG assembly, enhanced wound closure, or cell proliferation. Although B␤ 1-42 was not necessary for matrix assembly, it was required for matrix-FBG-enhanced cell migration. These data indicate that FBG serves as an important matrix constituent in the absence of fibrin formation to enhance wound repair and implicate B␤ 1 IntroductionImmediately following disturbances in homeostasis, such as infection, tissue injury, or immunologic disorders, the host responds by activation of a conserved set of nonadaptive defense mechanisms that constitute the innate immune system. These nonadaptive defenses include cellular immunity via activated neutrophils and macrophages, activation of complement, and induction of the acute phase response (APR). 1 The APR is characterized by a series of local and systemic reactions that result in activation of various cell types to produce cytokines such as interleukin-1␤ (IL-1␤), IL-6, and tumor necrosis factor-␣ (TNF-␣). The cytokines in turn act on distant tissues and cells, resulting in fever, production of glucocorticoids, proliferation of cells of the immune system, and changes in synthesis of plasma proteins produced by the liver. Fibrinogen (FBG) is a well-characterized acute phase protein that is upregulated as part of the innate immune response to inflammation. 1 During coagulation, adhesive glycoproteins from plasma become incorporated into the fibrin clot by covalent cross-linking providing, in addition to the hemostatic plug, a scaffold for cell migration and proliferation; a reservoir for growth factors, proteases, and protease inhibitors; and a substrate for induction and modulation of cell function. 2 Although FBG is regarded primarily for its hemostatic role in platelet aggregation and fibrin clot formation, we have shown that expression of the FBG genes and production of the intact protein occurs in pulmonary alveolar epithelial cells in response to inflammation...

The progression of a tumor from benign and localized to invasive and metastatic growth is the major cause of poor clinical outcome in cancer patients. Much like in a healing wound, the deposition of fibrin(ogen), along with other adhesive glycoproteins, into the extracellular matrix (ECM) serves as a scaffold to support binding of growth factors and to promote the cellular responses of adhesion, proliferation, and migration during angiogenesis and tumor cell growth. Inappropriate synthesis and deposition of ECM constituents is linked to altered regulation of cell proliferation, leading to tumor cell growth and malignant transformation. Fibrin deposition occurs within the stroma of a majority of tumor types. In contrast, abundant FBG, not fibrin, is present within the stroma of breast cancers. It is thought to originate from exudation of plasma FBG and subsequent deposition into the tumor stroma and not endogenous synthesis and secretion of FBG by breast tumor cells. However, we show that MCF‐7 human breast cancer cells synthesize and secrete FBG polypeptides, suggesting that the origin of FBG in the stroma of breast carcinoma may be due to endogenous synthesis and deposition. Moreover, FBG assembles into ECM as conformationally altered FBG, not as fibrin. Studies in our laboratory demonstrate that FBG alters the ability of breast cancer cells to migrate. Together, the results of studies from our laboratory, as well as the laboratories of others, indicate that the presence of fibrin(ogen) within the tumor stroma likely affects the progression of tumor cell growth and metastasis. This review focuses on FBG within tumors and its relationship with other tumor constituents, ultimately focusing on the role of FBG in breast cancer.

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This study investigated student learning outcomes using a case-based approach focused on cellular respiration. Students who used the case study, relative to students who did not use the case study, exhibited a significantly greater learning gain, and demonstrated use of higher-order thinking skills. Preliminary data indicate that after engaging with the case study, students were more likely to answer a question addressing misconceptions about cellular respiration correctly when compared with students who did not use the case study. More rigorous testing is needed to fully elucidate whether case-based learning can effectively clarify student misconceptions related to biological processes.

Evolution of the domain encoding the V1/V2 variable region of the simian immunodeficiency virus sm (SIVsm) envelope (env) gene was analyzed in relation to route of virus challenge, virus load, and neutralizing antibody (NAb) titers during primary infection of rhesus macaques with the pathogenic SIVsmE660 isolate. In this model system animals are initially infected with multiple viruses as evidenced by the presence of multiple V1/V2 genotypic variants that could be resolved by using a heteroduplex tracking assay (HTA). Overlapping subsets of the multiple variants were established in each animal. There was no selection for the establishment of specific variants in comparing intravenous-and intrarectal-challenged macaques at week 2 postinfection, suggesting that no genotypic selection occurred at the mucosal surface. There was an initial period of significant stability of the V1/V2 variants. Macaques challenged intravenously displayed subsequent V1/V2 diversification significantly earlier than macaques challenged intrarectally and well past the initial resolution of viremia. The time when SIVsmE660-specific NAbs reached a threshold titer of 100 was significantly correlated with the timing of V1/V2 diversification, even though antibodies to the Env protein could be detected much earlier. The time when NAbs reached a titer of 400 was significantly correlated with virus load late in infection. These results show that the route of infection affects the timing of V1/V2 diversification and that this diversification is correlated with the maturation of a specific NAb response. However, prior immunization capable of priming an anamnestic Env antibody response did not accelerate V1/V2 diversification. This result suggests that diversification of the SIV env V1/V2 region is the result of a type-specific antibody response.Both the human immunodeficiency virus type 1 (HIV-1) and the simian immune virus (SIV) envelope (Env) proteins contain variable regions (12, 34). The V1/V2 variable regions are a multifunctional domain on Env that undergoes a conformational change upon CD4 binding (46,56), modulates exposure of the coreceptor binding site on Env (55), can contribute to cell tropism and cytopathicity (20,42), and contains epitopes for antiviral antibodies (22,31,49). The V1/V2 region, along with the other variable regions, represents regions of the viral genome that express remarkable capacity to evolve in response to changing selective pressures within the host.Systemic and mucosal infection represent two major routes of HIV-1 entry into human hosts. Several studies have examined viral evolution in relation to route of infection (29,48,50,51). These results suggested that mucosal barriers act as selective filters for HIV-1 genotypes.The development of host neutralizing antibodies (NAbs) as part of the humoral response against HIV-1 and SIV most often occurs after the resolution of peak plasma viremia (43,45). The variable regions on the HIV-1 and SIV Env proteins can serve as linear and conformational epitopes for NAbs (1,9,...